Elucidating the Functional Mechanisms by Which the Protein Tyrosine Phosphatase SHP2 Is Involved in the Pathogenesis of Systemic Lupus Erythematosus
Abstract
Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disorder. However, how SLE occurs remains unknown. >50 patients with Noonan Syndrome (NS), a congenital disorder mediated by gain-of-function mutations in SHP2, developed SLE, suggesting correlation between phosphatase activity and systemic autoimmunity. We measured SHP2 activity in lupus-prone MRL/lpr mouse spleens, and found that phosphatase activity was significantly increased. Moreover, SHP2 activity was increased in lupus patient peripheral blood mononuclear cells (PBMCs), suggesting SHP2 activity is causal to SLE. We next utilized an SHP2 inhibitor, 11a-1, and showed that treated MRL/lpr mice and SLE patient T cells reduced proliferation of T cells and decreased production of interferon gamma (IFNgamma) and interleukin 17A/F (IL17A/F). Importantly, normalized SHP2 activity in lupus-prone mice increased lifespan, suppressed glomerulonephritis, reduced spleen size, and diminished skin lesions, implicating SHP2 in lupus associated immunopathology. How this occurs remains unclear. We hypothesize that increased SHP2 activity in SLE causes aberrant T cell signaling, inducing proliferation and production of pro-inflammatory cytokines to mediate organ damage. Our Aims will assess signaling pathways and cytokine subsets aberrantly regulated in SLE by SHP2 in 1) lupus-prone mice and 2) human SLE; and 3) investigate whether use of an allosteric SHP2 inhibitor can treat SLE patients. In Year 1, we found that T cell-specific expression of SHP2 is a critical driver of SLE pathology, specifically in the regulation of double negative (DN) T cells. These data suggest that SHP2 deletion improves physiological outcomes and slows the progression of SLE pathophysiology. Working to develop either a systemic or targeted inhibitor for SHP2 may yield a potent, novel, and specific treatment for SLE.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2023
- Accession Number
- AD1225074
Entities
People
- Maria I. Kontaridis